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ADME
Intro Many drugs fail because of ADME issues. It is a problem that medicinal chemists have strong organic chemistry skills, but lack the anatomy/physiology The metabolism of (orally administired) drug molecules is similar to food ingested. Hence the digestion process is a key principle underlying drug ADME. 4 stages of drug Disposition Absorption Distribution Metabolism Excretion (see discussion on Elimination vs Excretion Absorption and Distribution are often considered together Elimination is sometimes described as the sum of Metabolism + Excretion ADME issues lead to bioavailability issues for oral administired drugs. Some drug have a very low biavailability (pyridostigmine for chemical warfare treatment) An important task of medicinal chemistry is to understand and identify how ADME causes loses to the bioavailability of the drug molecules to the target site. Hence it is important to understand the route taken by a drug from administration to excretion/elimination. The Digestive system is setup in what is effectively a series of stages. Each organ has controlled pH, enzymes and co-enzymes which are switched on/off as appropriate. Mechanical stirring in a bath of enzymes. permeability is an important concept (parameter in ADME) Drug Absorption Intro the route or method by which the drug reaches the blood supply diffusion penetration of membranes binding to plasma proteins partition into fat Drug Distribution The body has barriers and the body has clearance systems to remove drugs distribution of drugs into different bodily compartments blood drugs are rapidly distributed by the blood supply To Tissues To Cells Drug Metabolism the liver is the main organ for drug metabolism can undergo metabolism in the bile and general circulation there are over 30 known CYPs only 6 have the highest impact on drug discovery. Enzymes other than CYPs can also metabolise drugs. Definition metabolism is the breakdown of the parent drug into metabolites normally metabolites are eliminated from the body Physical processes First pass metabolism, Phase 1 metabolism, Phase 2 metabolism A drug can either induce or inhibit CYPs which leads to alarming drug–drug interaction combinations. Drug Excretion Lungs bile duct in bile sweat kidneys For usage/confusage see Elimination vs Excretion overview from S807 The task of a medicinal chemist is to diagnose where the major losses have occurred in the ADME process and to make suitable modifications to the molecule in order to minimise the fragility of the drug. In order to make a good diagnosis, one needs a clear picture of the route taken by a drug. organs involved in ADME barriers intestinal barrier & permeability clearance permeability vs p-gp =Lipinski Rules= Lipinski Rules refers to the 5 rules (guidelines) of drug Hepatic portal vein it has been estimated that a human being possesses 150,000 km 10 blood carrying tubes (enough to go round the earth four times). Interestingly, after a meal, blood flow increases by 30 to 130% of basal flow and the hyperaemia is confined to the segment if the intestine exposed to the chyme. a significant proportion of a drug arriving into the liver will partition or be transported into the hepatocyte, where it may be metabolised by hepatic enzymes to inactive chemicals during the initial trip to the liver by what is known as the first pass effect. The Kidneys nephrons notes humans process ~30 tonnes of food in a lifetime production of complex molecules such as bile acids glycogen catabolises fats Drug metabolism is similar to food metabolism key issues solubility